Process of cleaving 9, 11 oxido steroids with alcohols and organic acids



United States PROCESS OF CLEAV'ING 9,11 'OXIDO STEROIDS WITH ALCOHOLSAND ORGANIC ACIDS Josef Fried, New Brunswick, N.J., assignor to OlinMathieson Chemical Corporation, New York, N.Y., a

corporation of Virginia N Drawing. Filed July 29, 1954, Ser. No. 446,667

6 Claims. (Cl. 260-39745) derivatives having an oxy substituent in the9a-position.

One of the objects of this invention is the provision of certainsteroids of the pregnane (including the pregnene, and allopregnane)series useful in the preparation of other physiologically-activesteroids and also useful for their own physiological action.

The compounds of this invention comprise steroids of the pregnane serieshaving a 9a-MO substituent, and an ll-keto or llfi-hydroxy substituent,M being a member of the group consisting of hydrogen, a hydrocarbonradical and an acyl radical. Specifically preferred compounds are thosewherein M is a member of the group consisting of hydrogen, lower alkyl,and lower alkanoyl.

The process of this invention essentially comprises conveiting a913,1lB-oxido steroid, prepared by the methods disclosed hereinafter andin Serial No. 343,243 and my continuation-in-part thereof, Serial No.417,489, filed March 10, 1954, now Patent No. 2,852,511, into thecorresponding 9a-MO, llp-hydroxy steroid; the latter may then beoxidized to the corresponding ll-keto derivative.

Among the compounds of this invention are those of the general formula:

wherein the 4,5 position is double-bonded or saturated (a double bondbeing preferred), and R is H, R is OH, or together R and R is :0 or agroup convertible thereto by hydrolysis (R and R as keto beingpreferred), R" is H, R is fi-OH, or together R" and R is =0, M ishydrogen, a hydrocarbon radical (such as alkyl, alkenyl, aralkyl andcycloalkyl), or an acyl radical (such as alkanoyl, aralkanoyl, aromaticacyl, cycloalkyl acyl, alkyl-sulfonyl, aralkyl-sulfonyl, aromaticsulfonyl, and cycloalkyl-sulfonyl), Y is H, halogen, OH, or -O- (acyl),and Z is H, .or a-OH. The preferred compounds are those wherein M is ahydrogen, lower alkyl, or a lower alkanoyl radical.

The steroids of the'pregnane series having a 9OL-MO 'substituent and'anll-keto or llfl-hydroxy substituent, contrary-to what would have beenpredicted, possess Corticoid activity in a liver glycogen assay.

atnt

The 95,11fi-oxido compounds used as starting materials in the process.of this invention are prepared from the corresponding9a-bromo-ll/3-hydroxy derivatives as disclosed in Serial Nos. 343,243and 417,489, by reacting said 9a-bromo-11B-hydroxy derivatives with asuitable reagent. Reagents useful in this connection include, interalia, the alkali metal salts of lower allcanoic acids (e.g. potassiumacetate, sodium propionate, potassium butyrate), alkali metal carbonates(e.g. potassium bicarbonate, sodium carbonate, and sodium bicarbonate),and alkalis (e.g. potassium hydroxide and sodium hydroxide).

The conversion of the 9 3,1l/3-oxido compounds to the desired9a-MO,11fi-hydroxy compounds may be effected by reacting said oxidocompound with a compound of the formula MOH, wherein M is as abovedefined. Suitable compounds of the formula MOH, useful for the purposesof theinvention, include, inter alia, water; alcohols, such as loweralkanols (e.g. methanol, ethanol, n-propanel, and n-butanol),aralkanols"(e.g. benzyl alcohol and 2-phenylethanol), alkenols (e.g.vinyl alcohol and 3- butenol-l), and cycloalkanols (e.g. cycloh'exylalcohol and cyclopentyl alcohol); carboxylic acids, such as lowerialkanoic acids (e.g. acetic acid and propionic acid), aralkanoic acids(e.g. phenylacetic acid and hydrocinnamic acid), alkenoic acids,aromatic carboxylic acids (e.g. benzoic acid and naphthoic acid), andcycloalkyl carboxylic acids; the thione analogs of these carboxylicacids; sulfonic acids, such as lower alkane sulfonic acids (e.g. methanesulfonic acid, ethane sulfonic acid), andkane sulfonic acids, alkenesulfonic acids, aromatic sulfonic acids (e.g. benzene sulfonic acid,toluene sulfonic acid, and naphthalene sulfonic acid), and cycloalkanesulfonic acids.

The reaction may be carried out at various temperatures, the range ofroom temperature to reflux being suitable. The reaction may be carriedout either in the absence of a solvent or in a suitable solvent such asdioxane, acetone, tetrahydrofuran, etc. The use of a solvent ispreferred when both reactants are solids, or when the oxido steroid isnot soluble in the second reactant as is the case when MOI-I is water.The resulting product is isolated from the reaction mixture by methodsknown in the art.

The reaction is preferably carried out in the presence of a strong acid.Although strong acids such as sulfuric and "nitric are utilizable, theacids employed are prefer- *ably'those which do not form esters with thellfi-hydroxy ticularly preferred.

The 9a-MO,11B-hydroxy steroids obtained in the practice of thisinvention may be oxidized to the corresponding keto compounds byconventional oxidizing procedures, e.g. chromic acid in glacial aceticacid.

Among the 9,8,11,8-oxido steroids of the pregnane series utilizable inthe process of this invention are 95,11floxido-progesterone,95,1lB-oXido-Zl-hydroxy-progesterone, 9,8,1l 3-oxidol7a-2l-dihydroxy-progesterone, 9/3,1lfi-oxido-17fl-hydroxy-progesterone, and in the cases wherein there ispresent a 2l-hydroxy radical, the acyl derivatives thereof. The last areexemplified by the lower alkanoyl esters (e.g. acetyl, propionyl, andbutyryl), the aromatic esters (e.g. benzoyl and naphthoyl), and thesulfonyl esters (e.g. methane sulfonyl, ethane sulfonyl and benzenesulfonyl) For a clearer understanding of the foregoing general andfollowing detailed description of the invention, reference is made tothe following schematic analysis (proceeding from the9aabromollp-hydroxy steroid of the pregnane series, the derivation ofthis starting material 3 being the subject of the aforementionedapplications, Serial No. 343,243 and No. 417,489):

The following examples are illustrative of the invention, preliminaryExamples A-E illustrating the preparation of the 9,8,llfi-oxide startingcompounds, and Examples 1-6 illustrating preparation of the final 9oc-MOsteroids of this invention (all temperatures being in centigrade):

EXAMPLE A A -pregnene-9/3J1 3-0xid0 17a, 21 dial-3,20-dz'one (V) from9u-br0m0-A -pregnene-l1fl,17u,21-triol-3,20-dione ZJ-acetate (I) To asolution of 115 mg. 9abromo-A -pregnene-11 3, l7a,21-triol-3,20-dione21-acetate (obtainable as described in Example 1 of said applicationSerial No. 417,- 489) in 10 ml. methanol is added a solution of 103 mg.potassium bicarbonate in 1 ml. water. The resulting solution is allowedto remain at room temperature for 18 hours, after which time 4 ml. wateris added, and the solution is freed from methanol in vacuo. Chloro-formis added to the residue, and after mixing and separation of the layers,the chloroform solution is washed with Water and dried over sodiumsulfate. Evaporation of the solvent leaves a residue (about 82 mg.)which crystallizes readily from acetone. The pure A pregnene-9fi,l1}3-oxido-17a,21-diol-3,20 dione has the following properties: M.P., about206-208 C.; MI +23 (c., 0.75 in CHClg) Analysis-Calculated for 0, 11, 0,70.02; H, 7.77. Found (approximately): C, 70.39; H, 7.95.

4 EXAMPLE B M-pregnene-Ql-ZJIfi-oxido l7u,21 dial-3,20-di0ne acerate(VI) from 9u-br0mo-A -pregnene-1.Ifl,1 70:,21-11'1'01- 3,20-dz'one21-acetate (I) A solution of 2.5 g. of 9a-bromo-A -pregnene-11,8,17a,2l-triol-3,20-dione 21-acetate and 6.25 g. potassium acetate in 190absolute alcohol is refluxed for 50 minutes. After the addition of 20ml. water, the solution is concentrated in vacuo to incipientcrystallization. Water is again added (50 ml.) and the crystallizationis completed in the refrigerator. The first crop (about 1.31 g.) meltsat about 2095-105"; and a second crop (about 291 mg), melting at about206-98, is obtained on concentration of the mother liquors. Theanalytically pure material obtained by crystallization fi'om acetone,melts at about 210-12 and has MI +41 (c., 0.70 in CHCI xgg; 243 m (615,500)

Its approximate analysis (calculated for C H O C, 68.63; H, 7.51): C,69.02; H, 7.42.

EXAMPLE C A -pregnene-9BJ1fl-0xid0 21 ol-3,20-dione ZI-acetate (VII)from Qa-bromo-corticostercme acetate (II) A solution of 253.8 mg. of9a-bromocorticosterone acetate (obtainable as described in Example 3 ofapplication Serial No. 417,409) and 625 mg. of anhydrous potassiumacetate in 18 ml. of absolute alcohol is refluxed for 50 minutes. Afterthe addition of 10 ml. of water, the alcohol is evaporated in vacuo, andthe residual aqueous suspension extracted with chloroform. Thechloroform solution is washed with water, dried over sodium sulfate, andevaporated to dryness in vacuo. The residue (about 205 mg), an oil whichdoes not crystallize, is A pregheme-9,8,1lfl-oxido-21-ol-3,20-dione21-acetate.

EXAMPLE D 9 8,] lfi-oxido progesterone (VIII) from 9oz-br0mo-1Ifl-hydroxy-progesterone (III) 103 mg. 9m-bromo-l1B-hydroxy progesterone(obtainable as described in Example 2 of application Serial No. 417,489)is treated with 250 mg. of potassium acetate as described in Example B.The resulting amorphous product, 913,11/3-oxido progesterone (about 90.6mg), cannot be crystallized even after chromatography, and is thereforeused in the examples hereinafter without further purification.

EXAMPLE E A -pregnene-9/3,llfi-oxido-l 7a-ol-3,20-dione (IX) from9a-bromo-I15,]7a-dihydraw-progesterone (IV) A solution of 247 mg. of9a-.bromo-l1p,17u-dihydroxyprogesterone (obtainable as described inExample 19 of application Serial (No. 417,489) and 630 mg. of anhydrouspotassium acetate is refluxed for minutes. The reaction mixture isWorked up as described in Example A. The resulting crude residue isrecrystallized from acetone-hexane yielding pure A*-pregnene-98,11B-oxido- 17oc-0l3,20-Cli0ne of the following properties: M.P. 197-199 C., M1 +6 (c., 0.32 in chloroform);

3.05,. on 5.89,. 20-00 6.04.. (A -3-ketdne) Analysis.'Calcd. forC21H2804 (344.44): C, 73.22; H, 8.18. Found: C, 72,99; H, 8.11.

EXAMPLE 1: 9m-hydroxyhydrocortisone acetate (X) A solution of 408 mg. ofA -pregnene-9fi,11B-oxido 17a,21-diol-3,20-dione 21-acetate (VI) in amixture con taining 24 ml. of dioxane, 4 ml. of 1.1 N sulfuric acid and60 ml. of water is refluxed for 45 minutes. During this period of timethe rotation of the solution changes S than an initial value of +41 to avalue of 149. The .addition of 40 ml. of chloroform causes separation ofphases, and after separating oif the water layer, the,dioxane-chloroform (lower) layer is washed with Water, dilute sodiumbicarbonate solution and again with water. The washed extract is driedover sodium sulfate and evaporatedto dryness. in vacuo. The cruderesidue (about 417 mg.) is :acetylated M l-1111.2 ml. of aceticanhydrideand 2 ml. of pyridine for 1% hours. Evaporation of the acetylatingreagents in-high vacuum leaves a residue (about 396 mg.) which ischromatographed on 7 g. of silica gel. Elution of the chromatogram withchloroform (800 ml.) affords a fraction (about 110 mg.) which afterseveral recrystallizations from acetone-hexane melts at 218-219 C. Itrepresents a A -dehydrohydrocortisone acetate. hal +104 (c., 0.49 inchloroform);

R32; 241 m (e=15,400); A532 3.01 5.80 s, 591p,

Analysis.--Calcd. for C H O C, 68.63; H, 7.51. Found: C, 68.72; H, 7.26.

This substance shows about 0.4 times the activity of cortisone acetatein the rat liver glycogen assay.

Further elution of the chromatogram with 10% acetone in chloroformyields in the first 125 ml. a mixture which cannot be readily separatedby crystallization. In the next 1000 ml. this same eluant affords ahomogeneous crystalline fraction (about 110 mg.) which afterrecrystallization from acetone-hexane yields pure 9oc-hYd10XYhY-drocortisone acetate having the following properties: M.P. 216-217 C.;M1 +149 (c., 0.89 in acetone);

A123; 242 me (e: 16,400); aim? 2.99,, 5.84 6.18

Analysis.Calcd. for C23H3207 (420.49): C, 65.69; H, 7.67. Found: C,65.85; H, 7.57.

9a-hydroxyhydrocortisone acetate is about 0.2 times as active ascortisone acetate in the rat liver glycogen assay.

9a-hydroxyhydrocortisone acetate may also be produced by a modificationof the process of the above example, by substituting perchloric acid forsulfuric acid and conducting the experiment at room temperature, ratherthan at reflux.

EXAMPLE 2 Qa-methmyhydrocortisone acetate (XI) To a solution of 200 mg.of A -pregnene-9B,11B-oxidol7a,2l-diol-3,20-dione ZI-acetate (VI) in 10ml. of methanol is added 0.075 ml. of 72% perchloric acid. The mixtureis allowed to stand at room temperature for hours during which time thespecific rotation rose from 0 to 145. The mixture is drowned in an equalvolume of water containing enough sodium bicarbonate to render thesolution slightly basic, and the methanol is evaporated off in vacuo.The residual aqueous suspension is extracted with chloroform and thechloroform extract washed with water. Evaporation of the acetylatingreagents in vacuo furnishes material which crystallizes readily fromabsolute alcohol, M.P. about 208-209 C.; [111 +156 (c., 0.80 inchloroform);

a353,; 243 my. (=14,800);

Analysis.Calcd. for C24H3407: C, 66.34; H, 7.89; OCH 7.14. Found: C,65.91; H, 8.08; OCH 7.28.

EXAMPLE 3 Qa-ethoxyhydrocortz'sone acetate (XII) mus.

; minutes.

recrystallized from acetone-hexane and yieldsabout mg. of the pureethoxy derivative, M.P. about 144-145 C., [M +133 (0., 0.62 inchloroform).

Analysis.-Calcd. for C25H3607: C, 69.94; H, 8.09; OC H 10.03. Found: C,66.94; H, 7.89; OC H 8.43.

By substituting .n-butanol and iso-butanol for methanol in Example 2,the corresponding 9a-n-butoxyhydrocortisone acetate and9a-iso-butoxyhydrocortisone acetate are. produced, respectively.

EXAMPLE 4 9a-acetoxyhydrocortisone acetate (XIII) To a solution of 300mg. of A -pregnene-9fi,1lfl-oxidol7cc;21-diOl-3,20-d10116 21-acetate(VI) in 30 ml. of glacial acetic acid is added 0.225 ml. of 72%perchloric acid, and the mixture allowed to stand at room temperaturefor 5 After the addition of water and sufiicient sodium bicarbonate toneutralize the perchloric acid, the solution is concentrated tonear-dryness and extracted with chloroform. The chloroform residue iswashed with dilute sodium bicarbonate and with water and dried oversodium sulfate. Evaporation of the chloroform in vacuo leaves a residue,which on recrystallization from alcohol melts at about 233-23580.9a-acetoxyhydrooortisone acetate possesses about 0.5 times the activityof cortisone acetate in the liver glycogen assay.

9a-acetoxyhydrocortisone acetate may also be produced by a modificationof the process of the above example, by substituting sulfuric acid forperchloric acid and conducting the reaction at reflux temperature.

9a-hydroxyhydrocortisone acetate (X), 9e-methoxyhydrocortisone acetate(XI) 9u-ethoxyhydrocortisone acetate (XII), and 9a-acetoxyhydrocortisoneacetate (XIII) may each be hydrolyzed with a dilute acid such ashydrochloric acid or a dilute base such as sodium hydroxide, to form thecorresponding free 21-hydroxy derivative, namely,9a-hydroxyhydrocortisone (XIV), 9u-methoxyhydrocortisone (XV),9a-ethoxyhydrocortisone (XVI), and 9oL-flC6lIOXYhYdIO0OI-li8011t:(XVII), respectively.

EXAMPLE 5 9a-hydr0xyc0rtis0ne acetate (XVIII) To a solution of 29.5 mg.of 9a-hydroxy-hydrocortisone acetate (X) in 2 ml. of glacial acetic acidis added a solution of 5.76 mg. of chromic acid in 1.25 ml. of aceticacid. After 20 minutes, 1 ml. of methanol is added and the resultingmixture is concentrated in vacuo. The residue is distributed betweenchloroform and water and the resulting chloroform extract is Washed withWater, sodium bicarbonate solution and again with water. After dryingover sodium sulfate and evaporation of the solvent in vacuo, the residue(about 21.2 mg.) on crystallization from 95% alcohol, yields pure9a-hydroxycortisone acetate having the following properties: M.P. about237-239 C.; +205 (c., 0.51 in chloroform);

EXAMPLE 6 Qa-methoxycortisone acetate (XIX) 25 mg. of9a-methoxyhydrocortisone acetate is oxidized in 3 ml. of glacial aceticacid with 9.5 mg. of CrO for 35 minutes, by the procedure described inExample 5. A crystalline residue results, which is recrystallized fromacetone, M.P. about 243-245 0.; [06113 +186 (c., 0.62 in chloroform);

xjgg 239 mu (6=14,600);

Nuiol men '(XII), and 9a-acetoxyhydrocortisone acetate (XIII) areoxidized to 9oc-ethoxycortisone acetate (XX) and 90aacetoxy'cor-tisoneacetate (XXI), respectively. Each of these acetates, as well as9u-hydroxycortisone acetate (XVIII) and 9a-methoxycortisone acetate()GX), can be hydrolyzed with dilute acid such as hydrochloric acid toform the corresponding free 21-hydroxy derivatives, namely9a-hydroxycortisone (XXII), 9u-methoxycortisone (XXIII),9u-ethoxycortisone (XXW); and 9u-acetoxycortisone (XXV).

The invention may be variously otherwise embodied Within the scope ofthe appended claims.

I claim:

1. The process for producing a steroid of the pregnane series whichcomprises reacting a steroid of the general formula wherein Y isselected from the group consisting of hydroxy, halogen, hydrogen andlower alkanoyloxy, and Z is selected from the group consisting ofhydrogen and alpha-hydroxy, with a compound selected from the groupconsisting of lower alkanols, and lower alkanoic acids and recoveringthe product produced.

2. The'process of claim 1, wherein the reaction is carried out in thepresence of a strong acid.

3QThe process of claim 2 wherein the strong acid is perchloric acid.

4. The process of preparing 9a-methoxyhydrocortisone acetate whichcomprises reacting A -pregnene-9fi,11[3- oxido-l7a,21-diol-3,20dioneacetate with methanol.

'5. The process for preparing 9a-ethoxyhydrocortis0ne acetate whichcomprises reacting A -pregnene-9B,11fl- OXidO-l7oz,21-di0l3,20-di0n6acetate with ethanol.

6. The process for preparing 9m-acetoxyhydrocortisone acetate whichcomprises reacting A -pregnene-9fi,11 6- OXidO-17oc-Z1-diOl-3,20-di0fl6acetate with glacial acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,183,589 Reichstein Dec. 19, 1939 2,312,344 Logemann Mar. 2, 1943FOREIGN PATENTS 894,117 Germany 0a. 22, 1953 OTHER REFERENCES Heymann etal.: Jour. Am. Chem. Soc. 73, pp. 5252- 1951 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No 2 949 478 August 16 1960 Josef FriedIt is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 2 line 59 for "NB- read l'Tcacolumn 6, line 4 for "69.,94" read6634 --'a Signed and sealed this 4th day of April 1961:.

(SEAL) An ERNEST W. SWIDER XXXXdi ARTHUR w. CROCKER Attesting OfiicerActing Commissioner of Patents

